Heterocyclic compounds

ABSTRACT

Heterocyclic compounds of the general formula:    &lt;IMAGE&gt;  (I)  wherein, Z represents methylene group or sulfur atom, R represents a general formula: G-E-D-B-A-L represents a group of general formula: -CO-COR2 -CO-R4 -CO-CH2-COR2 -CO-CF2-COR2 -CO-CO-NR5R6 or -CO-CH2-CO-NR5R6 and non-toxic salt or hydrate thereof possess an inhibitory activity on propyl endopeptidase, and therefore useful, for prevention and/or treatment of amnesia.

This is a a divisional application of prior application No. 08/008,365,filed Jan. 22, 1993, now U.S. Pat. No. 5,401,760, which is a divisionalapplication of 07/700,299, filed May 15, 1991, now U.S. Pat. No.5,212,191, which is a divisional of 07/333,227, filed on Apr. 5, 1989,now U.S. Pat. No. 5,053,414.

SUMMARY

The present invention is related to novel compounds having an inhibitoryactivity on prolyl endopeptidase.

More particularly, this invention is related to

1) novel heterocyclic compounds having an inhibitory activity on prolylendopeptidase, of the following general formula: ##STR2## wherein, allof the symbols have the same meaning as hereafter defined 2) processesfor the preparation of them, and

3) anti-amnesia agents containing them an active ingredient.

BACKGROUND

Recent advances in neuroscience are making clear the natural shape ofneurotransmitter substances deeply related to memory in the brain. It issaid that some of these substances are neuropeptides containingprolines.

Recovery of the memory was reported by the dosing neuropeptidecontaining proline to experimental amnesia rats (See Science 211, 601(1981)).

On the other hand, it is presumed that these neuropeptide-hormones shallbe metabolized by cerebral endogenous peptidases. Especially, prolylendopeptidase (EC, 3. 4. 21. 26) might take part in these metabolismsclosely (See J. Biochem., 94, 1179 (1983)).

From these facts, the studies were in progress that it should bepossible to prevent or treat amnesia by inhibiting prolyl endopeptidaseand suppressing the metabolism of neurotransmitters. (See Protein,Nucleic acid and Enzyme 25(6), 513(1980); Nippon Nougei Kagaku Kaishi58(11), 1147(1984); J. Neurochem., 41, 69(1983); ibid 42, 237(1984).)

For the purpose described above, several compounds were synthesized. Forexample, it is clear thatN-benzyloxycarbonyl-glycyl-L-prolyl-chloromethane,N-benzyloxycarbonyl-L-prolyl-prolinal strongly inhibit prolylendopeptidase (See J. Neurochem., 41, 69 (1983)). More recently, it isdisclosed that the compounds shown below are effective for the abovepurpose.

(i) Pyrrolidine derivatives of general formula: ##STR3## wherein, R¹represents ##STR4## R² represents lower alkyl group, phenyl group whichis unsubstituted or substituted or --CH₂ --R²².

With the proviso that, R³, R⁴, R⁵ independently represent hydrogen atom,halogen atom, hydroxy group, lower alkyl group, phenyl group which isunsubstituted or substituted, --CH₂ R⁹, --X--R¹⁰, --O--CO--R¹², --NH₂,--NHR¹⁴ or NR¹⁷ R¹⁸, with the proviso that R⁹ represents phenyl groupwhich is unsubstituted or substituted. X represents an oxygen atom orsulfur atom. R¹⁰ represents lower alkyl group, phenyl group which issubstituted or unsubstituted or --CH₂ R¹¹, with the proviso that R¹¹represents phenyl group which is unsubstituted or substituted. R¹²represents lower alkyl group, phenyl group which is unsubstituted orsubstituted or --CH₂ R¹³, with the proviso that R¹³ represents phenylgroup which is unsubstituted or substituted. R¹⁵ represents lower alkylgroup, cycloalkyl group of 5 or 6 ring members, phenyl group which isunsubstituted or substituted, --CH₂ R¹⁵, with the proviso that R¹⁵represents phenyl group unsubstituted or substituted.) or --CO--R¹⁶ withthe proviso that R¹⁶ represents lower alkyl group or phenyl group whichis unsubstituted or substituted R¹⁷ and R¹⁸ independently representlower alkyl group or --CH₂ R¹⁹, with the proviso that R¹⁹ representsphenyl group which is unsubstituted or substituted.

R⁶ represents a hydrogen atom or lower alkyl group. R⁷ represents ahydrogen atom, lower alkyl group, benzyl group, CH₃ --CH(OH)--or--(CH₂)_(n) --R²⁰, with the proviso that n represents an integer of from0 to 4. R²⁰ represents ##STR5## with the proviso that R²¹ representshydrogen atom, lower alkyl group or benzyl group, or heterocyclic ringgroup. R⁸ represents hydrogen atom or 5-membered heterocyclic ring grouptogether with R⁷ and nitrogen atom and carbon atom which areneighboured. R²² represents phenyl group which is unsubstituted orsubstituted. See Japanese Patent Kokai No. 62-221666, i.e., EuropeanPatent Publication No. 238319.

ii) Pyrrolidine derivatives of its general formula: ##STR6## wherein, R¹represents ##STR7## with the proviso that, R³, R⁴ and R⁵ independentlyrepresent hydrogen atom, halogen atom, hydroxy group, lower alkyl group,phenyl group which is unsubstituted or substituted, --CH₂ R⁹, --X--R¹⁰,--CO--R¹², --NH₂, NHR¹⁴ or --NR¹⁷ R¹⁸, with the proviso that R⁹represents phenyl group which is unsubstituted or substituted. Xrepresents an oxygen atom or sulfur atom. R¹⁰ represents lower alkylgroup, phenyl group which is unsubstituted or substituted, or --CH₂ R¹¹,with the proviso that R¹¹ represents phenyl group which is unsubstitutedor substituted. R¹² represents lower alkyl group, phenyl group which isunsubstituted or substituted or --CH₂ R¹³, with the proviso that R¹³represents phenyl group which is unsubstituted or substituted. R¹⁴represents lower alkyl group, cycloalkyl group of 5 or 6 rings members,phenyl group which is unsubstituted or substituted, --CH₂ R¹⁵, with theproviso that R¹⁵ represents phenyl group which is unsubstituted orsubstituted, or --CO--R¹⁶, with the proviso that R¹⁶ represents loweralkyl group, or phenyl group which is unsubstituted or substituted. R¹⁷and R¹⁸ independently represent lower alkyl group or --CH₂ R¹⁹, with theproviso that R¹⁹ represents phenyl group which is unsubstituted orsubstituted. R⁶ represents hydrogen atom or lower alkyl group. R⁷represents hydrogen atom, lower alkyl group, benzyl group, CH₃--CH(OH)-- or --(CH₂)_(n) --R²⁰, with the proviso that n represents aninteger of from 0 to 4. R²⁰ represents --OH, --SH, --NH₂, --SCH₃,##STR8## --CONH₂, --NH--C(=NH)--NH₂, --CO₂ R²¹, with the proviso that,R²¹ represents hydrogen atom, lower alkyl group or benzyl group, orheterocyclic ring group, R⁸ represents hydrogen atom, or 5-memberedheterocyclic ring group together with R⁷ and a nitrogen atom and carbonatom which are neighboured. R²² represents hydrogen atom, lower alkylgroup, phenyl group which is unsubstituted or substituted, or --CH₂ R²⁴with the proviso that R²⁴ represents phenyl group which is unsubstitutedor substituted. R²³ represents or when R²³ and R²³ are each takentogether, they represent lower alkylene group or lower alkylene group.See Japanese Patent Kokai No. 62-221667, i.e., European PatentPublication No. 238319.

The present inventors have also filed an application related to prolinalderivatives having an activity of anti-amnesia, in advance of thepresent application, i.e.:

(iii) Prolinal derivatives of general formula: ##STR9## wherein Arepresents alkylene or alkenylene group of from 1 to 8 carbon atom(s) ora saturated hydrocarbon ring of from 3 to 7 carbon atoms, R representshydrogen atom, phenyl group, benzyl group, alkyl group of from 1 to 8carbon atom(s) or cycloalkyl group of from 3 to 7 carbon atoms,

B represents alkylene group of from 1 to 8 atom(s) unsubstituted orsubstituted by phenyl group or benzyl group or a single bond,

D represents carbocyclic or heterocyclic ring unsubstituted orsubstituted by from one to three of halogen atom, alkyl or alkoxy groupof from 1 to 4 carbon atom(s), nitro group or trifluoromethyl group. SeeJapanese Patent Application No. 62-290631, i.e., European PatentPublication No. 268190.

COMPARISON WITH THE PRIOR ART

The compounds of the present invention of the general formula (I) arenovel compounds which have new modifications.

More concretely, each groups of the compounds of the general formulafrom (Ic) to (If) shown below which corresponds to the group R of thecompounds of the general formula (I) are new substituents. It was firstfound that the compounds of the general formula from (Ic) to (If)possess an inhibitory activity on prolyl endopeptidase by the presentinventors.

The compounds of the general formula (Ia) and (Ib) are also novel.

The present inventors tried to modify the group D of the compounds ofthe general formula (C) in our application described hereinbefore. Weconfirmed that the compounds wherein the benzene ring was converted toanother ring (including heterocyclic rings, fused rings, e.g.naphthalene, fluorence, furan etc.) also have the inhibitory activity onprolyl endopeptidase.

As the group G in the general formula (I) corresponds to the group D ofthe general formula (C), it is not difficult to expect that thecompounds wherein the benzene ring as the group G was replaced by another ring will possess the inhibitory activity on prolyl endopeptidase,when the compounds of the present invention wherein the group G is abenzene ring possess the inhibitory activity.

DISCLOSURE OF THE INVENTION

The present invention is related to:

1) A heterocyclic (pyrrolidine derivative or thiazolidine derivative)compound of the general formula: ##STR10## wherein, Z representsmethylene group or sulfur atom, R represents the general formula:

    G--E--D--B--A--

wherein, A represents a bond, alkylene group of from 1 to 6 carbonatom(s), alkenylene group of from 2 to 6 carbon atoms, a group of thegeneral formula: ##STR11## wherein, Y represents alkylene group of from1 to 4 carbon atom(s) or alkenylene group of from 2 to 4 carton atoms ora saturated hydrocarbon ring of from 4 to 7 carbon atoms or heterocyclicmono ring. B represents a bond or alkylene group of from 1 to 6 carbonatom(s). D represents a bond, oxygen atom, carbonyl group or a group ofthe general formula:

    --NR.sup.1 --CO-- or --CO--NR.sup.1 --

wherein, R¹ represents hydrogen atom, alkyl group of from 1 to 6 carbonatom(s), phenyl group or benzyl group.

E represents a bond, alkylene group of from 1 to 8 carbon atom(s) oralkylene group of from 1 to 8 carbon atom(s) substituted by phenyl orbenzyl group.

G represents a carbocyclic or heterocyclic ring which is unsubstitutedor substituted by 1˜3 of alkyl group of from 1 to 6 carbon atom(s),alkoxy group of from 1 to 6 carbon atom(s), halogen atom,trifluoromethyl group or nitro group.

L represents a group of the general formula: ##STR12## wherein, R²represents hydrogen atom, hydroxy group, alkyl group of from I to 6carbon atom(s), alkoxy group of from 1 to 6 carbon atom(s), phenylgroup, alkyl group of from 1 to 6 carbon atom(s) substituted by phenylgroup or alkoxy group of from 1 to 6 carbon atom(s) substituted byphenyl group.

R³ represents alkyl group of from 1 to 6 carbon atom(s), phenyl group,or alkyl group of from 1 to 6 carbon atom(s) substituted by phenylgroup.

R⁴ represents alkyl group of from 1 to 6 carbon atom(s), phenyl group,alkyl group of from 1 to 6 carbon atom(s) substituted by phenyl group ortrifluoromethyl group.

R⁵ and R⁶ independently represents hydrogen atom, alkyl group of from 1to 6 carbon atom(s), phenyl group, or alkyl group of from 1 to 6 carbonatom(s) substituted by phenyl group.

With the proviso that the following compounds are excluded:

(i) Compounds wherein both of A and B are bonds.

(ii) Compounds wherein Z is methylene group, and t is a group of generalformula: ##STR13## wherein all of the symbols are the same meaning as inhereinbefore defined.

and

R is

(1) a group of general formula:

    G'--E--CONH--B--A--

(2) a group of general formula:

    G'--CO--B--A--

(3) a group of general formula: ##STR14## (4) a group of generalformula:

    G'--O--Alk--

(5) a group of general formula: ##STR15## (6) a group of generalformula:

    G'--Alk--

(7) a group of general formula: ##STR16## (8) a group of generalformula: ##STR17## wherein, G' represents benzene ring which isunsubstituted or substituted by substituent(s).

Alk represents a bond or alkylene group of from 1 to 3 carbon atom(s).

p represents an integer of from 1˜5 and non-toxic salts or hydratethereof

2) Processes for the preparation of them; and

3) Anti-amnesia agents containing them as an active ingredient.

The following groups of compounds are included in the present invention,that is: ##STR18## wherein, L¹ represents a group of the generalformula:

    --CO--R.sup.4

    --CO--CH.sub.2 --COR.sup.2

    --CH(OH)--COR.sup.2

    --CO--CF.sub.2 --COR.sup.2

    --CH(OH)--CF.sub.2 --COR.sup.2

    --CO--CO--NR.sup.5 R.sup.6 or

    --CO--CH.sub.2 --CO--NR.sup.5 R.sup.6

wherein all of the symbols are the same meaning as hereinbefore defined.

L² represents a group of the general formula: ##STR19## wherein all ofthe symbols are the same meaning as hereinbefore defined. A' representsa bond, alkylene group of from 1 to 6 carbon atom(s), alkenylene groupof from 2 to 6 carbon atom(s), or a group of the general formula:##STR20## wherein, Y represents alkylene group of from 1 to 4 carbonatom(s) or alkenylene group of from 2 to 4 carbon atoms.

a saturated hydrocarbon ring of from 4 to 7 carbon atoms or heterocyclicmono ring containing two hetero atoms.

E' represents alkylene group of from 1 to 8 carbon atom(s), alkylenegroup of from 1 to 8 carbon atom(s) substituted by phenyl or benzylgroup.

Alk' represents alkylene group of from 4 to 20 carbon atoms.

In the general formula (I) and (Id), "alkylene group of from 1 to 6carbon atom(s)" represented by A, A' and B means methylene, ethylene,trimethylene, tetramethylene, pentamethylene and hexamethylene groupsand isomers thereof.

In the general formula (I), (Id) and (Ie), "alkylene group from 1 to 8carbon atom(s)" represented by E and E' means groups described aboveincluding heptamethylene and octamethylene groups and isomers thereof.

In the general formula (I), "alkylene group of from 1 to 4 carbonatom(s)" represented by Y means methylene, ethylene, trimethylene andtetramethylene group and isomers thereof.

In the general formula (I), "alkenylene group of from 2 to 4 carbonatoms" represented by Y means vinylene, propenylene, butenylene andbutadienylene groups and isomers thereof.

In the general formula (I) and (Id), "alkenylene group of from 2 to 6carbon atoms" represented by A and A' means groups described aboveincluding pentenylene, pentadienylene, hexenylene, hexadienylene andhexatrienylene groups and isomers thereof.

In the general formula (I) and (Id), "saturated hydrocarbon ring of from4 to 7 carbon atoms" represented by A and A' means cyclobutane,cyclopentane, cyclohexane and cycloheptane.

In the general formula (I), heterocyclic mono ring represented by Ameans aromatic rings of from 3 to 7 ring members and wherein 1 or 2hetero atom(s), which may be partially or fully saturated.

Examples of the rings mentioned above are furan, thiophene, pyrrole,oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole,furazane, pyran, pyridine, pyridazine, pyrimidine, pyrazine rings andpartially or fully saturated rings thereof.

In the general formula (I), preferred heterocyclic rings represented byA especially are piperidine, pyrrolidine and thiazolidine rings.

In the general formula (Id), heterocyclic mono ring containing twohetero atoms means aromatic rings containing from 3 to 7 ring memberswhich may be partially or fully saturated.

Examples of the rings mentioned above are oxazole, isoxazole, thiazole,isothiazole, imidazole, pyrazole, furazone, pyridazine, pyrimidine,pyrazine rings and partially or fully saturated rings thereof.

In the general formula (I), preferred heterocyclic ring represented byA' especially is thiazolidine ring.

In the general formula (If), "alkylene group of from 4 to 20 carbonatoms" represented by Alk' means tetramethylene, pentamethylene,hexamethylene, heptamethylene, octamethylene, nonamethylene,decamethylene, undecamethylene, dodecamethylene, tridecamethylene,tetradecamethylene, pentadecamethylene, hexadecamethylene,heptadecamethylene, octadecamethylene, nonadecamethylene,eicosamethylene groups and isomers thereof.

In the general formula (I), "alkylene group of from 1 to 3 carbonatom(s)" represented by Alk means methylene, ethylene, trimethylenegroup and isomers thereof.

In the general formula (I) "alkyl group of from 1 to 6 carbon atom(s)"represented by R¹, R², R³, R⁴, R⁵ and R⁶ means methyl, ethyl, propyl,butyl, pentyl and hexyl groups and isomers thereof.

In the general formula (I), "alkyl group of from 1 to 6 carbon atom(s)"in G and G' means the same as above.

In the general formula (I), "alkoxy group of from 1 to 6 carbon atom(s)"in R², G and G' means methoxy, ethoxy, propoxy, butoxy, penthyloxy andhexyloxy groups and isomers thereof.

In the general formula (I), "halogen atom" in G and G' means chlorine,bromine, fluorine and iodine atoms.

In the general formula (I), "carbocyclic ring" represented by G meansmono-, di- or tri-cyclic aromatic carbocyclic ring(s) containing notmore than 15 carbon atoms which may be partially or fully saturated.

Examples of the rings mentioned above are benzene, naphthalene, indene,azulene, fluorene, phenanthrene, anthracene, acenaphthalene, biphenylenerings and partially or fully saturated rings thereof.

In the general formula (I), "heterocyclic ring" represented by G meansmono-, di- or tri-aromatic heterocyclic ring(s) containing not more than15 carbon and hetero atoms which may be partially or fully saturated. Inabove heterocyclic rings, rings containing one or two of hetero atom(s)are preferred.

Examples of the rings mentioned above are furan, thiophene, pyrrole,oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, furazan,pyran, pyridine, pyridazine, pyrimidine, pyrazine, indole, isoindole,benzofuran, benzothiophene, indolizine, chromene, quinoline,isoquinoline, quinolizine, purine, indazole, quinazoline, cinnoline,quinoxaline, phthalazine, pteridine, carbazole, acridine,phenanthridine, xanthene, phenazine, phenothiazine rings and partiallyor fully saturated rings thereof.

In the general formula (I), preferred ring represented by G especiallyare benzene, naphthalene, fluorene, pyridine, furan, isoquinoline andacridine rings and partially saturated rings thereof.

In the above rings, substituted benzene rings are preferred assubstituted rings by substituent(s).

In the present invention, hetetro atom(s) in the heterocyclic ring(s)means nitrogen, oxygen and sulfur atoms.

Throughout the specification including the claims, stereo isomersgenerated by stereo configuration(s) (asymmetric carbon, double bondetc.) and structural isomers generated by branching of a carbon chain,etc., are included in the present invention.

For example, it may be easily understood that alkylene and alkenylenegroups include straight-chained and also branched-chained ones, to theskilled in the art.

Rings represented by A or rings in G may be attached to the adjacentgroup at any position.

NON-TOXIC SALTS

Among the compounds of the present invention of the general formula (I),compounds wherein L contains carboxy group may be converted into thecorresponding salts. Non-toxic and water-soluble salts are preferable.Suitable salts, for example, are the following: salts of alkaline metals(sodium, potassium, etc.), salts of alkaline earth metals (calcium,magnesium, etc.), ammonium salts, salts of pharmaceutically acceptableorganic amines (tetramethylammonium, triethylamine, methylamine,dimethylamine, cyclopentylamine, benzylamine, phenethylamine,piperidine, monoethanolamine, diethanolamine, tris(hydroxymethyl)amine,lysine, arginine, N-methyl-D-glucamine etc.). The, the present inventionalso includes hydrate.

Process for the preparation of the compounds of the present invention(1)

Among the compounds of the present invention of the general formula (I),compounds of the general formula: ##STR21## wherein, L²¹ represents agroup of general formula:

    --CO--COR.sup.2, --CH(OH)--COR.sup.2 or --CO--CONR.sup.5 R.sup.6

wherein, all of the symbols have the same meaning as hereinbeforedescribed, and the other symbols are the same meaning as hereinbeforedefined,

may be prepared by processes described in the following reaction scheme[A].

Symbols in each formula represent the following meaning or ashereinbefore defined.

R²¹ : alkoxy group of from 1 to 6 carbon atom(s) ##STR22##

All of the reactions in the scheme [A] are known reactions; briefdescriptions are the following:

Step <a> is N-acylation, and it may be carried out, for example, usingbenzoyl chloride and an aqueous solution of alkali (sodium bicarbonate,etc.) in a water-miscible organic solivent (acetone, etc.).

Step <b> is oxidation, and it may be carried out, for example, by methodof Swern oxidation or Jones' oxidation.

Step <c> is hydrocyanation, and it may be carried out, for example,using sodium cyanate, in the presence of an acid (hydrochloric acid,etc.), in a water-miscible organic solvent (THF, etc.).

Step <d> is hydrolysis, and it may be carried out, for example, byrefluxing in the presence of an acid (hydrochloric acid, etc.).

Step <e> is esterification, and it may be carried out; for example,using thionyl chloride or hydrochloride gas in a corresponding alcohol(methanol, ethanol, etc.)

Step <f> is a reaction to form amide, and it may be carried out, forexample, to convert a carboxylic acid of the general formula (VIII) intoa corresponding acid halide using an acid halogenating-agent (thionylchloride, oxalyl chloride, etc.), and the acid halide obtained wasreacted with an amine of the general formula (VII) in the presence of atertiary amine (triethylamine, etc.) in an inert organic solvent(methylene chloride etc.); or to convert a carboxylic acid of thegeneral formula (VIII) into an activated ester using a mixed acidanhydride (isobutyl chloroformate, ethylchloroformate, pivaloylchloroformate, etc.). and the ester obtained was reacted with an amineof the general formula (VII) in the presence or absence of a tertiaryamine (same as above).

Step <g> is oxidation, and it may be carried out, for example, by themethod of Swern oxidation or Jones' oxidation.

Step <h> is hydrolysis, and it may be carried out, for example, using anaqueous solution of alkali (potassium carbonate, sodium hydroxide, etc.)in a water-miscible organic solvent (methanol, etc.).

Step <i> is a reaction to form amide, and it may be carried out, forexample, using a chloroformic acid ester (isobutyl chloroformate, etc.)and a corresponding amine in the pressence of a tertiary amine.

Step <j> is esterification, and it may be carried out, for example,using a halogenating agent (benzyl bromide, alkyl bromides etc.), in thepresence of a base (potassium carbonate, triethylamine, etc.), in aninert organic solvent (DMSO, DMF, acetone, etc.).

Step <k> is hydrolysis, and it may be carried out by the procedure asdescribed in step <h>.

Step <l> is esterification, and it may be carried out by the sameprocedure as described in step <J>.

Step <m> is oxidation, and it may be carried out by the same procedureas described in step <g>.

Process for the preparation of the compounds of the present invention(2)

Among the compounds of the present invention of the general formula (I),compounds of general formula: ##STR23## wherein, L²² represents##STR24## the other symbols are the same meaning as hereinbeforedefined, may be prepared by processes described in the followingreaction scheme [B] or [C].

Symbols in each formula represents the following meaning or are ashereinbefore defined.

R⁴¹ : alkyl group of from 1 to 6 carbon atom(s), phenyl group, or alkylgroup substituted by phenyl group. ##STR25##

All of the reactions in scheme [B] and [C] are known reactions and briefdescriptions are the following:

Step <n> is Reformatskij reaction, and it may be carried out, forexample, by refluxing with a corresponding alkyl bromoacetate, in thepresence of zinc powder and iodine, in an inert organic solvent (THF,benzene etc.).

Step <o> is hydrolysis, and it may be carried out by the same procedureas discribed in step <h>.

Step <p> is mild-oxidation, and it may be carried out, for example,using Dess-Martin reagent, in an inert organic solvent (methylenechloride, etc.).

Step <q> is hydrolysis, and it may be carried out by the same procedureas described in step <h>.

Step <r> is a reaction to form amide, and it may be carried out by thesame procedure as described in step <i>.

Step <s> is Reformatskij reaction and it may be carried out by the sameprocedure as described instep <n>, using a corresponding alkylbromodifluoroacetate in stead of alkyl bromoacetate.

Step <t> is hydrolysis, and it may be carried out by the same procedureas described in step <h>.

Step <u> is mild-oxidation, and it may be carried out by the sameprocedure as described in step <p>.

Step <v> is a hydrolysis, and it may be carried out by the sameprocedure as described in step <h>.

Step <w> is a reaction to form acetal, and it may be carried out, forexample, using acid, catalyst (camphorsulphonic acid, p-toluenesulphonicacid etc.) in an alcohol (methanol, ethanol, etc.).

Step <x> is a reaction to form acetal, and it may be carried out, forexample, by refluxing with ethylene glycol, in the presence of an acidcatalyst (p-toluenesulphonic acid etc.), in an inert organic solvent(benzene, etc.).

Step <y> is Grignard reaction, and it may be carried out, for example,using a corresponding Grignard reagent (alkylmagnesium chloride, etc.)in an ether (THF etc.).

Step <Z> is oxidation, and it may be carried out by the same procedureas described in step <g>.

Step <aa> is fluoroalkylation, and it may be carried out, for example,using trifluoromethyl iodide under the irradiation of ultrasonic waves.

Step <bb> is oxidation, and it may be carried out by the same procedureas described is step <u>.

Starting materials and reagents in the present invention are known perse. For example, the compounds of the general formula (VIII) and (IX)are described with processes for the preparation in European PatentPublication No. 268190, 277588 or 280956 or Japanese Patent PublicationNo. 63-162672 or 63-264454.

Throughout the specification, in each reactions, products may bepurified by conventional methods, for example, distillation atatmospheric or reduced pressure, high performance liquid chromatography,thin layer chromatography using silica gel or magnesium silicate orwashing or recrystallization. Purification may be carried out after eachreaction or a series of reaction.

PHARMACOLOGICAL ACTIVITIES

The compounds of the present invention of the general formula (I)possess an inhibitory activity on prolyl endopeptidase, as describedbefore. For example, in a standard laboratory test, results in thefollowing were given.

Prolyl endopeptidase inhibitory activity in vitro

The compounds of the present invention showed activites as in thefollowing Table I, with the test system described hereafter.

                  TABLE I                                                         ______________________________________                                                       Concentration for                                              Example No. of 50% inhibition                                                 the compounds  IC.sub.50 (μM)                                              ______________________________________                                        2                  0.003                                                      2          (b)     0.0018                                                     2          (d)     0.00085                                                    2          (g)     0.0017                                                     2          (h)     0.017                                                      2          (l)     0.0018                                                     6                  3.0                                                        7                  0.0012                                                     9                  0.023                                                      12                 69                                                         13                 0.10                                                       15                 1.5                                                        15         (a)     0.12                                                       17         (a)     0.18                                                       19                 14                                                         ______________________________________                                    

Inhibitory activity of prolyl endopeptidase in vitro was measured by thefollowing test system.

A mixed solution of 20 mM tris-HCl buffer (pH 7.5 : 935 μl; containing10 mM EDTA and 10 mM mercaptoethanol), a solution of a compound of thepresent invention in DMSO (10 μl) and a solution of prolyl endopeptidasewhich was purified from bovine brain (0.13 unit ml; prepared by themethod described in J. Biochem., 94, 1179 (1983) ) in tris-HCl buffer(15 μl) was preincubated for 15 mins at 37° C.

To the solution, 5 mM ofN-benzyloxycarbonyl-glycyl-prolyl-p-nitroanilide (40 μl) in a mixture of40% dioxane - 60% water was added. The solution was incubated for 1 minat the same temperature.

Optical absorption (a₁) at 405 nm of the solution, and opticalabsorption (a₂) at 405 nm of the solution after 30 mins' more incubationat 37° C. were measured.

Optical absorptions (b₁ and b₂) of the solutions using DMSO instead ofthe solution of the compound of the present invention were alsomeasured.

Inhibitory ratio was calculated by the following expression and IC₅₀(required concentration for 50% inhibition) was obtained (See Protein,Nucleic acid and Enzyme 25(6), 513, 1980.). ##EQU1##

TOXICITY

On the other hand, it was confirmed that the toxicity of the compoundsof the present invention was very low. Therefore, the compounds of thepresent invention may be considered to be sufficiently safe and suitablefor pharmaceutical use.

APPLICATION FOR PHARMACEUTICALS

To inhibit prolyl endopeptidase is to suppress the metabolism ofneurotransmitters, substances taking part in memory in the brain (eachof them is a peptide.) described hereinbefore, and therefore should beuseful for prevention and/or treatment of amnesia, in animals includinghuman beings, especially human beings.

The compounds of the present invention possess an inhibitory activity onprolyl endopeptidase in vitro, so they are expected to be useful forprevention and/or treatment of amnesia.

For the purpose above described, the compounds of the present inventionmay normally by administered systemically or locally, usually by oral orparenteral administration.

The doses to be administered are determined depending upon age, bodyweight, symptom, the desired therapeutic effect, the route ofadministration, and the duration of the treatment, etc. In the humanadult, the doses per person per dose are generally between 1 mg and 500mg, by oral administration, up to several times per day, and between 1mg and 100 mg, by parenteral administration (preferably, intravenousadministration) up to several times per day.

As mentioned above, the doses to be used depend upon various conditions.Therefore, there are cases in which doses lower than or greater than theranges specified above may be used.

At the administration, the compounds of the present invention may beformed into solid compositions, liquid compositions or the othercompositions for oral administration, injection compositions, externalcompositions, suppositories, etc., for parenteral administration.

Solid compositions for oral administration include compressed tablets,pills, capsules, dispersible powders; and granules. In such solidcompositions one or more of the active compound(s) is or are, admixedwith at least one inert diluent (lactose, mannitol, glucose,hydroxypropylcellulose, micrycrystalline cellulose, starch,polyvinylpyrrolidone, magnesium metasilicate aluminate, etc.). Thecompositions may also comprise, as is normal practice, additionalsubstances other than inert diluents: e.g., lubricating agents(magnesium stearate etc.), disintegrating agents (cellulose calciumgluconate, etc.), assisting agents for dissolving (glutamic acid,aspartic acid, etc.) stabilizing and agents (lactose, etc.).

The tablets or pills may, if desired, be coated with a film of gastricor enteric material (sugar, gelatin, hydroxypropylcellulose orhydroxypropylmethyl cellulose phthalate etc.).

Capsules include soft ones and hard ones.

Liquid compositions for oral administration includepharmaceutically-acceptable solutions, emulsions, suspensions, syrupsand elixirs.

In such liquid compositions, one or more of the active compound(s) is orare used in inert diluent(s) commonly used in the art (purified water,ethanol, etc.).

Besides inert diluents, such compositions may also comprise adjuvants(wetting agents, suspending agents, etc.), sweetening agents, flavouringagents, perfuming agents and preserving agents.

Other compositions for oral administration include spray compositionswhich may be prepared by known methods and which comprise one or more ofthe active compound(s).

Spray compositions may comprise additional substances other than inertdiluents: e.g., stabilizing agents (sodium sulfite, etc.), isotonicbuffer (sodium chloride, sodium citrate, citric acid, etc.).

For preparation of such spray compositions, for example, the methoddescribed in the U.S. Pat. Nos. 2,868,691 or 3,095,355 may be used.

Injections for parenteral administration include sterile aqueous ornon-aqueous solutions, suspensions and emulsions. In such compositions,one or more of active compound(s) is or are admixed with at least one ofinert aqueous diluent(s) (distilled water for injection, physiologicalsalt solution, etc.) or inert non-aqueous diluent(s) (propylene glycol,polyethylene glycol, olive oil, ethanol, POLYSORBATE 80 (registeredtrade mark) etc.).

Injections may comprise other than inert diluents: e.g., preservingagents, wetting agents, emulsifying agents, dispersing agents,stabilizing agents (lactose, etc.), assisting agents such as assistingagents for dissolving (glutamic acid, aspartic acid, etc.).

They may be sterilized, for example, by filtration through abacteria-retaining filter, by incorporation of sterilizing agents in thecompositions or by irradiation. They may also be manufactured in theform of sterile solid compositions, for example, by freeze-drying, whichcan be dissolved in sterile water or some other sterile diluents forinjection immediately before use.

Other compositions for parenteral administration include liquids forexternal use, and endermic liniments (ointments, etc.), suppositoriesand pessaries which comprise one or more of the active compound(s) andwhich may be prepared by known methods.

REFERENCE EXAMPLES AND EXAMPLES

The following reference examples and examples are to illustrate thepresent invention, but not limit the present invention.

The solvents in the parentheses show the developing or eluting solventsand the ratios of the solvents used are by volume in chromatographicseparations.

Unless otherwise specified, "IR" were measured by a liquid film method.

REFERENCE EXAMPLE 1 Synthesis of (2S)-1-benzoylpyrrolidine-2-methanol##STR26##

Benzoyl chloride (18.5 ml) and an aqueous (50 ml) solution of sodiumcarbonate (17.0 g) were added dropwise to a solution of(S)-2-pyrrolidinemethanol (12.0 g) in a mixture of acetone (70 ml) andwater (14 ml). After addition, the reaction mixture was stirred for 30mins at room temperature. The reaction mixture was filtered. Water wasadded to the filtrate. The mixture was extracted with methylenechloride. The extract was washed, dried and evaporated. The residue waspurified by column chromatography on silica-gel (hexane-EtOAc) to givethe title compound (24.1 g) having the following physical data:

TLC: Rf 0.19 (EtOAc).

REFERENCE EXAMPLE 2 Synthesis of (2S)-1-benzoylpyrrolidin-2-al ##STR27##

A solution of DMSO (27.9 ml) in methylene chloride (50 ml) was added toa solution of oxalyl chloride (16.4 ml) in methylene chloride (300 ml)which was cooled to -70° C.

A solution of (2S)-1-benzoylpyrrolidine-2-methanol (24.1 g) in methylenechloride (120 ml) was added dropiwise to the solution at -70° C. Themixture was stirred for 30 mins. Triethylamine (89.5 ml) was addeddropwise to the reaction solution at -70° C. The mixture was stirred for50 mins at the same temperature, and then rised to 0° C. gradually.Water was added to the solution.

The mixture was extracted with methylene chloride. The extract waswashed, dried, and evaporated. The residue was purified by columnchromatography on silica gel (hexane-EtOAc) to give the title compound(23.7 g) having the following physical data:

TLC: RF 0.38 (EtOAc)

REFERENCE EXAMPLE 3 Synthesis of(2RS)-2-t(2S)-1-benzoylpyrrolidine)-2-hydroxyacetonitrile ##STR28##

(2S)-1-benzoylpyrrolidin-2-al (23.7 g) was dissolved into a mixture ofTHF (200 ml) and water (135 ml). Sodium cyanate (8.36 g) was added tothe solution.

Conc. hydrochloric acid (10 ml) was added to the mixture withice-cooling. The reaction mixture was stirred for 1 hr. at the sametemperature, and for 20 mins. at room temperature. Water was added tothe reaction mixture. The mixture was extracted with methylene chloride.The extract was washed, dried and evaporated to give the title compoundhaving the following physical data:

TLC: Rf 0.44 & 0.51 (EtOAc)

REFERENCE EXAMPLE 4 Synthesis of(2RS)-2-[(2S)-pyrrolidin-2-yl]-2-hydroxyacetic acid ##STR29##

Conc. hydrochloric acid (210 ml) was added to(2RS)-2-[(2S)-1-benzoylpyrrolidine)-2-hydroxyacetonitrile (21 mg). Themixture was refluxed for 1 hr.

The reaction solution was cooled to room temperature, and filtered. Thefiltrate was diluted with water. The solution was washed with ether. Thewater layer was absorbed onto an amberite column. The column was elutedwith aqueous ammonia.

The eluented solution was evaporated. The concentrate was dissolved inwater. The solution was treated with active carbon. The filtrate wasevaporated. The residue was cooled to -10° C. to deposit crystals. Thecrystals were gathered to give the title compound (5.84 g) having thefollowing physical data:

TLC: Rf 0.16 (EtOAc: AcOH: H₂ O=3:1: 1)

REFERENCE EXAMPLE 5 Synthesis of(2S)-1-[3-(N-benzyl-N-methylcarbamoyl)propanoyl]pyrrolidine-2-methanol##STR30##

Triethylamine (4.0 ml) and isobutyl chloroformate (1.86 ml) were addeddropwise to a solution of 3-(N-benzyl-N-methylcarbamoyl) propionic acid(2.5 g) in THF (30 ml) cooled to -20° C. The mixture was stirred for 30mins at the same temperature. Triethylamine (4 ml) was added to asolution of (S)-2-pyrrolidinemethanol (1.45 g) in THF (30 ml). To thesolution cooled to -25° C., the above solution was added dropwise.

The mixture was stirred for 1 hr at the same temperature. Afterreaction, water was added to the reaction solution. The mixture wasextracted with EtOAc. The extract was washed, dried and evaporated. Theresidue was purified by column chromatography on silica gel (CH₂ Cl₂--CH₃ OH) to give the title compound (2.59 g) having the followingphysical data:

TLC: Rf 0.24 (EtOAc: CH₃ OH=9:1)

REFERENCE EXAMPLE 6 Synthesis of(25)-1-(3-(N-benzyl-N-methylcarbamoyl)propanoyl)pyrrolidin-2-al]##STR31##

By the same procedure described in reference example 2, using(2S)-1-[3-(N-benzyl-N-methylcarbamoyl)propanoyl)pyrrolidine-2-methanol(2.59 g), the title compound (2.37 g) having the following physicaldata. was given:

TLC : Rf 0.40 (EtOAc: CH₃ OH=9:1)

EXAMPLE 1 Synthesis of (2RS)-2-[(2S)-1-[3-(N-benzyl-N-methylcarbamoyl)propanoyl]pyrrolidin-2-yl )-2-hydroxyacetic acid ethyl ester ##STR32##

Triethylamine (3.5 ml) and isobutyl chloroformate (980 μl) were added toa solution of 3-(N-methyl-N-benzylcarbamoyl) propionic acid (1.33 g) inTHF (16 ml). The mixture was stirred for 15 mins at -15° C. The solutionwas named solution A. (2RS)-2-[(2S)-pyrrolidin-2-yl)-2-hydroxyaceticacid (1.0 g) was dissolved in ethanol (25 ml). The solution was cooledto -20° C. Thionyl chloride (1.0 ml) was added dropwise to the cooledsolution. The mixture was stirred for 2 hrs. at room temperature.Triethylamine (5 ml) was added dropwise to the solution cooled to -20°C. again. The solution was allowed to stand to rise to room temperature,and evaporated.

THF (26 ml) and triethylamine (1.15 ml) were added to the residue. Tothe solution cooled to -10° C., the above solution A was added dropwise.The mixture was stirred for 2 hrs at room temperature. Water was addedto the reaction solution. The mixture was extracted with EtOAc. Theextract was washed, dried and evaporated. The residue was purified bycolumn chromatography on silica gel (hexane - EtOAc) to give the titlecompound (1.67 g) having the following physical data:

TLC: Rf 0.41 (CH₂ Cl₂ :CH₃ OH=9:1);

IR (CHCl₃ solution):

ν 3470˜3350, 3000, 1730, 1630, 1440, 1250˜1210, 1120 cm⁻¹.

EXAMPLE 1 (a)-1 (n)

By the same procedure as is described in title compounds having thephysical data shown in table II were given. ##STR33##

                                      TABLE II                                    __________________________________________________________________________    Example                                                                       No.  R                    Name              TLC       IR                      __________________________________________________________________________                                                          (νcm.sup.-1)         1 (a)                                                                              φ-(CH.sub.2).sub.9                                                                             2-[(2S)-1-(10-phenyldecanoyl)                                                                   Ref 0.34  3450˜3200,                                                              2900,                                             pyrrolidin-2-yl]-2-hydroxyacetic                                                                (hexane:EtOAc                                                                           2840, 1720, 1630,                                 acid ethyl ester  1:1)      1610, 1430, 1250,                                                             1180, 1100              1 (b)                                                                               ##STR34##           2-[(2S)-1-[3-[N-4- trifluoromethylphenylmethyl)-                               N-phenylcarbamoyl]propanoyl] pyrrolidin-2-yl]-2                              -hydroxyacetic acid ethyl ester                                                                 Ref 0.14 (hexane:EtOAc =                                                                3450˜3300,                                                              2950, 1720,                                                                   1650˜1610,                                                              1590, 1490, 1420,                                                             1390, 1315, 1260,                                                             1110, 1060, 1010,                                                             690                     1 (c)                                                                               ##STR35##           2-[(2S)-1-[3-[4-(4-phenylbutoxy) phenyl]propenoy                              l]pyrrolidin-2-yl]- 2-hydroxyacetic acid ethyl                                ester             Rf 0.26 (hexane:EtOAc =                                                                 2950, 1720, 1630,                                                             1580, 1500, 1410,                                                             1240, 1160, 820,                                                              690                     1 (d)                                                                               ##STR36##           2-[(2)-1-[3-[N-(4- chlorophenylmethyl)carbamoyl]                               propanoyl]pyrrolidin-2-yl]- 2-hydroxyacetic                                  acid etyl eter    Rf 0.31 (CH.sub.2 Cl.sub.2                                                    :CH.sub.3 OH                                                                            3300,                                                                         2990˜2930,                                                              1730, 1630, 1610,                                                             1550˜1530,                                                              1490, 1440˜143                                                          0, 1240, 1200,                                                                1095, 1015              1 (e)                                                                               ##STR37##           2-[(2S)-1-[3-[N-(9-fluorenyl) carbamoyl]propanoy                              l]pyrrolidin- 2-yl]-2-hydroxyacetic acid ethyl                                ester             Rf 0.42 (CH.sub.2 Cl.sub.2                                                    :CH.sub.3 OH                                                                            3460, 2990, 1725,                                                             1655, 1630, 1500,                                                             1445, 1370,                                                                   1245˜1205,                                                              1115                    1 (f)                                                                               ##STR38##           2-[(2S)-1-[(2RS)-2-isopropyl-7- phenylheptanoyl]                              pyrrolidin-2-yl]- 2-hydroxyacetic acid ethyl                                  ester             Rf 0.67 (hexane:EtOAc =                                                                 3350, 1720, 1600,                                                             1420, 1100, 1020,                                                             740, 690                1 (g)                                                                               ##STR39##           2-[(2S)-1-[3-[N-(1-naphthyl) methyl-N-methylcarb                              amoyl] propanoyl]pyrrolidin-2-yl]-2- hydroxyacet                              ic acid ethyl ester                                                                             Rf 0.33 (EtOAc:CH.sub.3 OH =                                                  19:1)     3350, 1720, 1620,                                                             1400, 1100, 790,                                                              670                     1 (h)                                                                               ##STR40##           2-[(2S)-1-[(1RS,2R)-2-(3- phenylpropanoyl)                                    cyclopentanecarbonyl]pyrrolidin-2- yl]-2-hydroxy                              acetic acid ethyl ester                                                                         Rf 0.56 (EtOAc:hexane =                                                                 3400, 1690, 1610,                                                             1420, 1180, 1090,                                                             1010, 740, 670          1 (i)                                                                               ##STR41##           2-[(2S)-1-[(1RS,2R)- 2-(N-benxylcarbamoyl)                                    cyclopentanecarbonyl)pyrrolidin-2- yl]-2-hydroxy                              acetic acid ethyl ester                                                                         Rf 0.20 (EtOAc:hexane =                                                                 3300, 1720, 1600,                                                             1510, 1420, 1220,                                                             1090, 1010, 670         1 (j)                                                                               ##STR42##           2-[(2S)-1-[3-[N-(2,4- dichlorophenylmethyl)carba                              moyl] propanoyl]pyrrolidin-2-yl]-2- hydroxyaceti                              c acid ethyl ester                                                                              Rf 0.35 (EtOAc:CH.sub.3 OH =                                                  19:1)     3300, 3050, 1710,                                                             1600, 1520, 1410,                                                             1240, 1180, 1090,                                                             1010, 810, 665          1 (k)                                                                               ##STR43##           2-[(2S)-1-[(2RS)-2-isopropyl-6-(4- methoxyphenyl                              )hexanoyl]pyrrolidin- 2-yl]-2-hydroxyacetic                                   acid ethyl ester  Rf 0.31 (hexane:EtOAc =                                                                 3300, 1720, 1600,                                                             1500, 1420, 1240,                                                             1100, 1020, 810,                                                              670                     1 (l)                                                                               ##STR44##                                                                                          ##STR45##        Rf 0.49 (CH.sub.2 Cl.sub.2                                                    :CH.sub.3 OH                                                                             ##STR46##              1 (m)                                                                               ##STR47##           2-[(2S)-1-[3-(N-benzyl-N- phenylcarbamoyl)propan                              oyl] pyrrolidin-2-yl]-2-hydroxyacetic acid                                    ethyl ester       Rf 0.48 (CH.sub.2 Cl.sub.2                                                    :CH.sub.3 OH                                                                            3450˜3350,                                                              2980, 1735, 1635,                                                             1595, 1495, 1405,                                                             1265, 1200, 1025,                                                             780, 730, 700           1 (n)                                                                               ##STR48##                                                                                          ##STR49##        Rf 0.29 (EtOAc:hexane =                                                                  ##STR50##              __________________________________________________________________________

EXAMPLE 2 Synthesis of2-[(2S)-1-[3-(N-benzyl-N-methylcarbamoyl)propanoyl]pyrrolidin-2-yl]-2-oxoaceticacid ethyl ester ##STR51##

DMSO (443 μl) was added dropwise to a solution of oxyalyl chloride (260μl) in methylene chloride (10 ml) cooled to -78° C. The solution wasstirred for 15 mins at the same temperature. A solution of(2RS)-2-((2S)-1-[3-(N-benzyl-N-methylcarbamoyl)propanoyl)pyrrolidin-2-yl]-2-hydroxyaceticacid ethyl ester (700 mg) in methylene chloride (6 ml) was addeddropwise to the solution at the same temperature. The mixture wasstirred for 20 mins. Triethylamine (1.42 ml) was added dropwise to thesolution. The solution was stirred for 10 mins at the same temperature,and for 30 mins. at 0° C.

Water was added to the reaction solution. The mixture was extracted withEtOAc. The extract was washed, dried and evaporated. The residue waspurified by column chromatography on silica gel (hexane - EtOAc) to givethe title compound (627 mg) having the following physical data:

TLC: Rf 0.18 (EtOAc);

IR (CHCl₃ solution):

ν 3000, 1725, 1630, 1440, 1205, 1050 cm⁻¹

EXAMPLE 2(a)-2(s)

By the same procedure as is described in example 2, title compoundshaving the physical data shown in table III were given. ##STR52##

                                      TABLE III                                   __________________________________________________________________________    Ex-                                                                           ample                                                 IR (νcm.sup.-1)      No. R                       Name            TLC       or                      __________________________________________________________________________                                                          mp                      2 (a)                                                                              ##STR53##              2-[(2S)-1-[3-[N-(4- chlorophenylmethyl)carbamo                                yl] propanoyl]pyrrolidin-2-yl]-2- oxoacetic                                   acid ethyl ester                                                                              Rf 0.18 (EtOAc)                                                                          ##STR54##              2 (b)                                                                              ##STR55##              2-[(2S)-1-[3-[N-(9-fluorenyl) carbamoyl]propan                                oyl]pyrrolidin- 2-yl]-2-oxoacetic acid ethyl                                  ester           Rf 0.31 (EtOAc)                                                                         mp                                                                            142˜146.degree                                                          . C.                    2 (c)                                                                             φ-(CH.sub.2).sub.9  2-[(2S)-1-(10-phenyldecanoyl)                                                                 Rf 0.48   3000˜2800,                                    pyrrolidin-2-yl]-2-oxoacetic                                                                  (EtOAc:hexane                                                                           1740˜1710,                                    ethyl ester     1:1)      1650˜1610,                                                              1430˜1400,                                                              1250,                                                                         1100, 1050, 740,                                                              690                     2 (d)                                                                              ##STR56##              2-[(2S)-1-[3-[N-(4- trifluoromethylphenylmethy                                l)-N- phenylcarbamoyl]propanoyl] pyrrolidin-2-                                yl]-2-oxoacetic acid ethyl ester                                                              Rf 0.14 (EtOAc:hexane =                                                                  ##STR57##              2 (e)                                                                              ##STR58##              2-[(2S)-1-[3-[4-(4-phenylbutoxy) phenyl]propen                                oyl]pyrrolidin-2-yl- 2-oxoacetic acid ethyl                                   ester           Rf 0.40 (EtOAc:hexane =                                                                  ##STR59##              2 (f)                                                                              ##STR60##                                                                                             ##STR61##      Rf 0.48 (EtOAc)                                                                          ##STR62##              2 (g)                                                                              ##STR63##              2-[(2S)-1-[3-(N-benzyl-N- phenylcarbamoyl)prop                                anoyl] pyrrolidin-2-yl]-2-oxoacetic acid                                      ethyl ester     Rf 0.49 (EtOAc)                                                                         2965, 1720, 1630,                                                             1400, 1355, 1260,                                                             1195, 1130, 1050        2 (h)                                                                              ##STR64##              2-[(2S)-1-[(2RS)-2-isopropyl-7- phenylheptanoy                                l]pyrrolidin-2-yl]- 2-oxoacetic acid ethyl                                    ester           Rf 0.44 & 0.40 (hexane:EtOAc                                                  = 7:3)    3000˜2900,                                                              2850, 1720, 1620,                                                             1430, 1260, 1050,                                                             740, 690                2 (i)                                                                              ##STR65##              2-[(2S)-1-[3-[N-(1-naphthyl) methyl-N-methylca                                rbamoyl] propanoyl]pyrrolidin-2-yl]-2-                                        oxoacetic acid ethyl ester                                                                    Rf 0.28 (EtOAc)                                                                         (CHCl.sub.3                                                                   solution) 2950,                                                               1715, 1625, 1430,                                                             1250˜1200,                                                              1040                    2 (j)                                                                              ##STR66##              2-[(2S)-1-[1RS,2R)- 2-(3-phenylpropanoyl)                                     cyclopentanecarbonyl]pyrrolidin- 2-yl]-2-oxoac                                etic acid ethyl ester                                                                         Rf 0.74 (EtOAc)                                                                         2900, 2840, 1700,                                                             1620, 1430, 1260,                                                             1050, 740, 690          2 (k)                                                                              ##STR67##              2-[(2S)-1-[(1RS,2R)-2-(N- benzylcarbamoyl)                                    cylopentanecarbonyl]pyrrolidin- 2-yl]-2-oxoace                                tic acid ethyl ester                                                                          Rf 0.45 & 0.52 (EtOAc)                                                                  3300, 2950, 2840,                                                             1720,                                                                         1660˜1610,                                                              1530, 1440,                                                                   1260˜1240,                                                              1130, 1050              2 (l)                                                                              ##STR68##              2-[(2S)-1-[3-[N-(2,4- dichlorophenylmethyl)car                                bamoyl] propanoyl]pyrrolidin-2-yl]-2-                                         oxoacetic acid ethyl ester                                                                    Rf 0.26 (EtOAc)                                                                         (CHCl.sub.3                                                                   Solution) 3450,                                                               2950, 1720, 1650,                                                             1620, 1500, 1430,                                                             1260˜1200,                                                              1090, 1040              2 (m)                                                                              ##STR69##              2-[(2S)-1-[(2RS)-2-isopropyl-6-(4- methoxyphen                                yl)hexanoyl]pyrrolidin- 2-yl]-2-oxoacetic                                     acid ethyl ester                                                                              Rf 0.55 & 0.62 (EtOAc:hexane                                                  = 1:1)    2940, 1720, 1620,                                                             1500, 1430,                                                                   1290˜1240,                                                              1050˜1030,                                                              820                     2 (n)                                                                              ##STR70##                                                                                             ##STR71##      Rf 0.60 (EtOAc:benzene =                                                                 ##STR72##              2 (o)                                                                              ##STR73##              2-[(2S)-1-[3-[N-(2-naphthyl) methyl-N-methylca                                rbamoyl] propanoyl]pyrrolidin-2-yl]-2-                                        oxoacetic acid ethyl ester                                                                    Rf 0.32 (EtOAc)                                                                         3000˜2900,                                                              1720˜1710,                                                              1620, 1420˜140                                                          0, 1250, 1100,                                                                1040, 810, 740          2 (p)                                                                              ##STR74##              2-[(2S)-1-[3-[N-(4- methylphenylmethyl)carbamo                                yl] propanoyl]pyrrolidin-2-yl]-2- oxoacetic                                   acid ethyl ester                                                                              Rf 0.54 (CH.sub.2 Cl.sub.2                                                    :CH.sub.3 OH                                                                            3300,                                                                         2980˜2910,                                                              1720, 1630, 1530,                                                             1440, 1260, 1050        2 (q)                                                                              ##STR75##              2-[(2S)-1-[3-N-(4- chlorophenylmethyl)-N-                                     phenylcarbamoyl]propanoyl] pyrrolidin-2-yl]-2-                                oxoacetic acid ethyl ester                                                                    Rf 0.31 (CH.sub.2 Cl.sub.2                                                    :CH.sub.3 OH                                                                            2980, 2870, 1725,                                                             1660˜1630,                                                              1595, 1490, 1425,                                                             1400, 1265, 1205,                                                             1135, 1090, 1055,                                                             1015, 800, 780,                                                               700                     2 (r)                                                                              ##STR76##              2-[(2S)-1-[3-[N-(4- chlorophenylmethyl)-N-                                    methylcarbamoyl]propanoyl] pyrrolidin-2-yl]-2-                                oxoacetic acid ethyl ester                                                                    Rf 0.24 (EtOAc)                                                                         2950, 2850, 1710,                                                             1620,                                                                         1480˜1400,                                                              1250,                                                                         1105˜1050,                                                              1000, 790               2 (s)                                                                              ##STR77##              2-[(2S)-1-[6-(2-napthyl)methyl- oxohexanoyl]py                                rrolidin-2-yl]- 2-oxoacetic acid ethyl                                                        Rf 0.44 (EtOAc:hexane =                                                                 1700, 1610, 1420,                                                             1250, 1050, 810,        __________________________________________________________________________                                                          740                 

EXAMPLE 3 Synthesis of2-[(2S)-1-[3-(N-benzyl-N-methylcarbamoyl)propanoyl]pyrrolidin-2-yl)-2-oxoaceticacid monohydrate ##STR78##

A mixture of 2-[(2S)-1-[3-(N-benzyl-N-methylcarbamoyl)propanoyl]pyrrolidin-2-yl]-2-oxoacetic acid ethyl ester (626 mg),potassium carbonate (277 mg), methanol (7 ml) and water (4 ml) wasstirred for 1 hr. at room temperature. Water was added to the reactionsolution. The mixture was extracted with EtOAc. The extract was washed,dried and evaporated to give the title compound (458 mg) having thefollowing physical data:

TLC : Rf 0.42 (EtOAc : AcOH : H₂ O)=3 :1 : 1);

IR (CHCl₃ Solution):

ν 3000, 1725, 1625, 1445 cm⁻¹

EXAMPLE 3(a)-3(r)

By the same procedure as is described in example 3, title compoundshaving the physical date shown in table IV were obtained. ##STR79##

                                      TABLE IV                                    __________________________________________________________________________    Example                                              IR (νcm.sup.-1)       No.  R-                   Name             TLC       or                       __________________________________________________________________________                                                         mp                       3 (a)                                                                               ##STR80##           2-[(2S)-1-[3-[N-(4- chlorophenylmethy)carbamoyl]                               propanoyl]pyrrolidin-2-yl]-2- oxoacetic                                                       Rf 0.35 (EtOAc:AcOH: H.sub.2                                                  O) = 3:1:1)                                                                             mp                                                                            160˜162°                                                          C.                      3 (b)                                                                               ##STR81##           2-[(2S)-1-[3-[N-(9-fluorenyl) carbamoyl]propanoy                              l]pyrrolidin- 2-yl]-2-oxacetic                                                                 Rf 0.44 (EtOAc:AcOH: H.sub.2                                                  O) = 3:1:1)                                                                             mp                                                                            212˜215°                                                          C.                      3 (c)                                                                               ##STR82##           2-[(2S)-1-[3-[N-(4- trifluoromethylphenylmethyl)                              -N- phenylcarbamoyl]propanoyl] pyrrolidin-2-yl]-                              2-oxoacetic acid Rf 0.10 (CHCl.sub.3 :CH.sub.3                                                 OH = 9:1) 3400˜3300,                                                              2890˜2840,                                                              1720, 1630˜1600                                                         , 1590, 1490,                                                                 1440˜1400,                                                              1320, 1160, 1105,                                                             1060, 1010, 700          3 (d)                                                                              φ-(CH.sub.2).sub.9-                                                                            2-[(2S)-1-(10-phenyldecanoyl) pyrrolidin-2-yl]-2                              -oxoacetic acid  Rf 0.10 (CHCl.sub.3 :CH.sub.3                                                 OH = 9:1) 3000˜2840,                                                              1720, 1580, 1440,                                                             1230, 1030, 690          3 (e)                                                                               ##STR83##           2-[(2S)-1-[3-[4-(4-phenylbutoxy) phenyl]propenoy                              l]pyrrolidin-2-yl]- 2-oxoacetic                                                                Rf 0.15 (CHCl.sub.3 :CH.sub.3                                                 OH = 4:1) 3000˜2800,                                                              1710, 1630, 1590,                                                             1500, 1420, 1240,                                                             1160, 810, 680           3(f)                                                                                ##STR84##                                                                                          ##STR85##       Rf 0.49 (EtOAc:AcOH: H.sub.2 O                                                = 3:1:1)                                                                                 ##STR86##               3 (g)                                                                               ##STR87##           2-[(2S)-1-[3-(N-benzyl-N- phenylcarbamoyl)propan                              oyl] pyrrolidin-2-yl]-2-oxoacetic                                                              Rf 0.49 (EtOAc:AcOH: H.sub.2 O                                                = 3:1:1)  (CHCl.sub.3                                                                   Solution) 2990,                                                               1725, 1635, 1595,                                                             1495, 1405               3 (h)                                                                               ##STR88##                                                                                          ##STR89##       Rf 0.08 (CHCl.sub.3 :CH.sub.3                                                 OH = 9:1)                                                                                ##STR90##               3 (i)                                                                               ##STR91##           2-[(2S)-1-[3-[N-(1-naphthyl) methyl-N-methylcarb                              amoyl] propanoyl]pyrrolidin-2-yl]-2- oxoacetic                                acid             Rf 0.05 (CHCl.sub.3 :CH.sub.3                                                 OH = 9:1) (KBr tablet)                                                                  3300˜3000,                                                              2900, 1720,                                                                   1630˜1590,                                                              1430˜1400,                                                              1230, 1030, 790,                                                              760                      3 (j)                                                                               ##STR92##           2-[(2S)-1-[(1RS,2R)-2-(3- phenylpropanoyl)                                    cyclopentanecarbonyl]pyrrolidin- 2-yl]-2-oxoacet                              ic acid          Rf 0.08 (CHCl.sub.3 :CH.sub.3                                                 OH = 9:1) (KBr tablet)                                                                  3500˜3400,                                                              2950, 1690, 1580,                                                             1440, 690                3 (k)                                                                               ##STR93##           2-[(2S)-1-[(1RS,2R)-2-(N- benzylcarbamoyl)                                    cyclopentanecarbonyl]pyrrolidin-2- yl]-2-oxoacet                              ic acid          Rf 0.05 (CHCl.sub.3 :CH.sub.3                                                 OH = 9:1) (KBr tablet)                                                                  3500˜3300,                                                              2950, 1720, 1610,                                                             1440, 1240, 1040,                                                             690                      3 (l)                                                                               ##STR94##           2-[(2S)-1-[3-[N-(2,4- dichlorophenylmethyl)carba                              moyl] propanoyl]pyrrolidin-2-yl]-2- oxoacetic                                 acid             Rf 0.05 (CHCl.sub.3 :CH.sub.3                                                 OH = 9:1) (KBr tablet)                                                                  3500˜3300,                                                              2950, 2900, 1720,                                                             1620, 1440, 1250,                                                             1040, 820                3 (m)                                                                               ##STR95##           2-[(2S)-1-[(2RS)-2-isopropyl-6-(4- methoxyphenyl                              )hexanoyl]pyr- rolidin-2-yl]-2-oxoacetic                                                       Rf 0.10 (CHCl.sub.3 :CH.sub.3                                                 OH = 9:1) 3500˜3300,                                                              2900, 1740˜1720                                                         , 1600˜1580,                                                            1500, 1440, 1230,                                                             1020, 810, 730, 690      3 (n)                                                                               ##STR96##                                                                                          ##STR97##       Rf 0.16 (EtOAc:CH.sub.3 OH =                                                  4:1)                                                                                     ##STR98##               3 (o)                                                                               ##STR99##           2-[(2S)-1-[3-[N-(2-naphthyl) methyl-N-methylcarb                              amoyl] propanyl]pyrrolidin-2-yl]-2- oxoacetic                                 acid             Rf 0.60 (EtOAc:AcOH: H.sub.2 O                                                = 3:1:1)  (KBr tablet)                                                                  3500˜3400,                                                              2900, 1710, 1610,                                                             1430, 1230               3 (p)                                                                               ##STR100##          2-[(2S)-1-[3-[N-(4- methylphenylmethylcarbamoyl]                               propanoyl]pyrrolidin-2-yl]-2- oxoacetic                                                       Rf 0.50 (EtOAc:AcOH: H.sub.2 O                                                = 3:1:1)  (CHCl.sub.3                                                                   Solution) 2990,                                                               2880, 1725, 1640,                                                             1595, 1490, 1400,                                                             1265, 1095, 1045,                                                             1015                     3 (q)                                                                               ##STR101##          2-[(2S)-1-[3-[N-(4- chlorophenylmethyl)-N-                                    phenylcarbamoyl]propanoyl] pyrrolidin-2-yl]-2-ox                              oacetic acid     Rf 0.56 (EtOAc:AcOH: H.sub.2 O                                                = 3:1:1)  (KBr tablet) 3300,                                                            2920, 1730, 1605,                                                             1560, 1460, 1110,                                                             1240, 1190, 1110,                                                             1060, 1035               3 (r)                                                                               ##STR102##          2-[(2S)-1-[3-[N-(4- chlorohenylmethyl)-N-                                     methylcarbamoyl]propanoyl] pyrrolidin-2-yl]-2-ox                              oacetic acid     Rf 0.10 (CHCl.sub.3 :CH.sub.3                                                 OH = 9:1) (CHCl.sub.3                                                                   Solution) 2950˜                                                         2840, 1710, 1620,                                                             1430,                    __________________________________________________________________________                                                         1390, 1080           

EXAMPLE 4 Synthesis of2-[(2S)-1-[3-(N-benzyl-N-methylcarbamoyl)propanoyl]pyrrolidin-2-yl]1-2-oxo-N-ethylacetamide##STR103##

A solution of 2[(2S)-1-[3-(N-benzyl-N-methylcarbamoyl)propanoyl)pyrrolidin-2-yl)-2-oxoacetic acid (98 mg) in THF (3 ml) wascooled to -20° C. Triethylamine (188 μl) and isobutyl chloroformate (77μl) were added dropwise to the solution. The mixture was stirred for 20mins at the same temperature. An aq. solution of ethylamine (70%; 200μl) was added dropwise to the solution at the same temperature. Thesolution was stirred for 1 hr, while the temperature of the solution wasraised to room temperature gradually. Water was added to the reactionsolution. The mixture was extracted with EtOAc. The extract was washed,dried and evaporated. The residue was purified by column chromatographyon silica gel (CH₂ Cl₂ --CH₃ OH) to give the title compound (62 mg)having the following physical data:

TLC : Rf 0.34 (EtOAc: AcOH : H₂ O=3 : 1 : 1);

IR : ν3300, 2980, 2940, 2875, 1730, 1630, 1520, 1435, 1375, 1355, 1240,1145, 1120, 1040 cm⁻¹

EXAMPLE 4(a)-4(b)

By the same procedure as is described in example 4, title compoundshaving the physical data shown in Table V were obtained.

                                      TABLE V                                     __________________________________________________________________________     ##STR104##                                                                   Example                                                                       No.  L         Name            TLC        IR (νcm.sup.-1)                  __________________________________________________________________________    4 (a)                                                                               ##STR105##                                                                              ##STR106##     Rf 0.37 (CH.sub.2 Cl.sub.2 :CH.sub.3 OH) =                                    0:1)                                                                                      ##STR107##                         4 (b)                                                                               ##STR108##                                                                              ##STR109##     Rf 0.19 (EtOAc)                                                                           ##STR110##                         __________________________________________________________________________

EXAMPLE 5 Synthesis of (2RS)-2-[(2S)-1-(3-(N-benzyl-N-methylcarbamoyl)propanoyl)pyrrolidin-2-yl)-2-hydroxyacetic acid monohydrate ##STR111##

By the same procedure as is described in example 3, using(2RS)-2-[(2S)-1-13-(N-benzyl-N-methylcarbamoyl)propanoyl)pyrrolidin-2-yl)-2-hydroxyaceticacid ethyl ester (670 mg), the title compound (517 mg) having thefollowing physical data was given.:

TLC : Rf 0.42 (EtOAc : AcOH : H₂ O=3 : 1 : 1);

IR (CHCl₃ solution):

ν3000, 1725, 1625, 1440 cm⁻¹

EXAMPLE 6 Synthesis of(2RS)-2-1(2S)-1-[3-(N-benzyl-N-methylcarbamoyl)propanoyl]pyrrolidin-2-yl]1-2-hydroxyaceticacid benzyl ester ##STR112##

A mixture of (2RS)-2-[(2S)-1-[3-(N-benzyl-N-methlcarbamoyl)propanoyl)pyrrolidin-2-yl)-2-hydroxyacetic acid (134 mg), potassiumcarbonate (64 mg), benzyl bromide (51 μl) and DMSO (1 ml) was stirredfor 1 hr at room temperature. Water was added to the mixture. Themixture was extracted with a mixture of hexane and EtOAc (1:1). Theextract was washed, dried and evaporated. The residue was purified bycolumn chromatography on silica gel (hexane-EtOAc) to give the titlecompound (141 mg) having the following physical data:

TLC : Rf 0.46 (CH₂ Cl₂ : CH₃ OH=1 : 1);

IR (KBr tablet):

ν3400˜3340, 2950˜2920, 1735, 1625, 1440˜1410, 1240, 1185, 1120 cm⁻¹

EXAMPLE 6(a)

By the same procedure as is described in example 6, title compoundhaving the physical data shown in table VI was given.

                                      TABLE VI                                    __________________________________________________________________________    Example                                                                       No.  Formula                     Name            TLC  IR                      __________________________________________________________________________                                                          (νcm.sup.-1)         6 (a)                                                                               ##STR113##                 2-[(2S)-1-[3-(N-benzyl-N- methylcarbamoyl                                     )propanoyl] pyrrolidin-2-yl]-2-oxoacetic                                      acid isobutyl ester                                                                           Rf 0.24 (EtOAc)                                                                    2950, 2870, 1720,                                                             1635, 1435, 1260,                                                             1120, 1055, 735,        __________________________________________________________________________                                                          695                 

EXAMPLE 7 Synthesis of2-[(2S)-1-[3-(N-benzyl-N-methylcarbamoyl)propanoyl]pyrrolidin-2-yl]-2-oxoaceticacid benzyl ester ##STR114##

By the same procedure as is described in example 2, using(2RS)-2-[(2S)-1-[3-(N-benzyl-N-methylcarbamoyl)propanoyl)pyrrolidin-2-yl]-2-hydroxyaceticacid benzyl ester (129 mg), the title compound (109 mg) having thefollowing physical data was given:

TLC : Rf 0.56 (CH₂ Cl₂ : CH₃ OH=10 : 1);

IR : ν2950˜2910, 1720, 1630, 1435, 1260, 1120, 1050 cm⁻¹

EXAMPLE 8 Synthesis of(1RS)-1-(2S)-1-13-(N-benzyl-N-methylcarbamoyl)propanoyl]pyrrolidin-2-yl)-2,2,2-trifluoroethanol##STR115##

Trifluoroiodomethane (2.3 g) was cooled to -78° C. with a trap. DMF (7ml), (2S)-1-[3-(N-benzyl-N-methylcarbamoyl)propanoyl]pyrrolidin-2-al(710 mg) and zinc (1.0 g) were added thereto. And the mixture wastreated with ultrasonic waves for 2 hrs. at room temperature. 1Nhydrochloric acid was added to the reaction solution. The mixture wasextracted with EtOAc. The extract was washed, dried, and evaporated. Theresidue was purified by column chromatography on silica gel (hexane -EtOAc) to give the title compound (217 mg) having the following physicaldata:

TLC:Rf 0.24 & 0.33 (EtOAc);

IR:ν 3300˜2250, 2920, 1735, 1690, 1640˜1610, 1440˜1400, 1375, 1265,1160, 1120 cm⁻¹

EXAMPLE 9 Synthesis of1-[(2S)-1-[3-(N-benzyl-N-methylcarbamoyl)propanoyl]pyrrolidin-2-yl]-2,2,2-trifluoroethan-1-one##STR116##

A mixture of (1RS)-1-[(2S)-1-13-(N-benzyl-N-methylcarbamoyl)propanoyl]pyrrolidin-2-yl ]-2,2,2-trifluoroethanol (103 mg), Dess-Martinreagent (435 mg) and methylene chloride (1.5 ml) was stirred for 3 hrs.at room temperature. After reaction, the raction solution was dilutedwith ether. The diluted solution was added dropwise to a saturated aq.solution of sodium bicarbonate (30 ml) wherein sodium thiosulfate (3.0g) was dissolved. The mixture was stirred for 10 mins at roomtemperature. The mixture was extracted with EtOAc. The extract waswashed, dried and evaporated. The residue was purified by columnchromatography on silica gel (hexane - EtOAc) to give the title compound(52 mg) having the following physical data:

TLC:Rf 0.32 (EtOAc);

IR:ν3270˜3150, 2920, 1730, 1630˜1600, 1445˜1405, 1260˜1240, 1160 cm⁻¹

EXAMPLE 10 Synthesis of(3RS)-3-[(2S)-1-(3-(N-benzyl-N-methylcarbamoyl)propanoyl]pyrrolidin-2-yl)-3-hydroxypropionicacid ethyl ester ##STR117##

Zinc powder (482 mg) and a small amount of iodine were added to asolution of ethyl bromoacetate (0.70 ml) in THF (6 ml). The mixture wasrefluxed for 30 mins. The solution was added dropwise to a solution of(2S)-1-[3-(N-benzyl-N-methylcarbamoyl)propanoyl)pyrrolidin-2-al (1.21 g)in benzene (10 ml). The mixture was refluxed for 30 mins. Afterreaction, 1N hydrochloric acid was added to the mixture. The mixture wasextracted with EtOAc. The extract was washed, dried, and evaporated. Theresidue was purified by column chromatography on silica gel(hexane-EtOAc) to give the title compound (1.21 g) having the followingphysical data:

TLC:Rf 0.38 (CH₂ Cl₂ :CH₃ OH=10:1);

IR:ν 3450˜3350, 2980, 1730, 1630, 1440˜1410, 1375, 1270˜1240, 1180˜1150,1110, 1030 cm⁻¹

EXAMPLE 11 Synthesis of3-[(2S)-1-(3-(N-benzyl-N-methylcarbamoyl)propanoyl]pyrrolidin-2-yl]-3-oxopropionicacid ethyl ester ##STR118##

A solution of (3RS)-3-[(2S)-1-[3-(N-benzyl-N-methylcarbamoyl)propionyl]pyrrolidin-2-yl]-3-hydroxypropionic acid ethyl ester (230 mg)in acetone (1 ml) was cooled to -30° C. Excess Jones' reagent was addeddropwise to the solution. The mixture was stirred for 1 hr at the sametemperature, and for 1 hr at -20° C., and for 1 hr at -10° C. Isopropylalcohol was added to the reaction solution. Water was added to themixture. The mixture was extracted with EtOAc. The extract was washed,dried, and evaporated. The residue was purified by column chromatographyon silica gel (hexane-EtOAc) to give the title compound (98 mg) havingthe following physical data:

TLC:Rf 0.50 (CH₂ Cl₂ :CH₃ OH=10:1);

IR:ν 2980˜2920, 1710, 1630, 1430˜1400, 1360, 1305, 1255, 1020 cm⁻¹

EXAMPLE 12 Synthesis of(3RS)-3-[(2S)-1-[3-(N-benzyl-N-methylcarbamoyl)propanoyl]pyrrolidin-2-yl]-3-hydroxy-2,2-difluoropropionicacid ethyl ester ##STR119##

A mixture of zinc powder (520 mg) and THF (8 ml) was refluxed. Asolution of ethyl bromo difluoroacetate (815 μl) in THF (6 ml) was addeddropwise to the solution. The mixture was refluxed for 2 mins. Asolution of(2S)-1-[3-(N-benzyl-N-methylcarbamoyl)propanoyl]pyrrolidin-2-al (800 mg)in THF (8 ml) was added dropwide to the solution. The mixture wasrefluxed for 10 mins. After cooling, a saturated aq. solution of sodiumbicarbonate was added to the solution. The mixture was extracted withEtOAc. The extract was washed, dried and evaporated. The residue waspurified by column chromatography on silica gel (hexane-EtOAc) to givethe title compound (754 mg) having the following physical data:

TLC:Rf 0.21 (EtOAc);

IR:ν 3270˜3200, 3000, 2925, 1780˜1760, 1635˜1605, 1440˜1425, 1375, 1310cm⁻¹

EXAMPLE 13 Synthesis of3-[(2S)-1-[3-(N-benzyl-N-methylcarbamoyl)propanoyl]pyrrolidin-2-yl]-3-oxo-2,2-difluoropropionicacid ethyl ester ##STR120##

A solution of (3RS)-3-[(2S)-1-[3-(N-benzyl-N-methylcarbamoyl)propanoyl)pyrrolidin-2-yl)-3-hydroxy-2,2-difluoropropionic acid ethylester (250 mg) in methylene chloride (1.5 ml) was added dropwise to asuspension of Dess-Martin reagent (448 mg) in methylene chloride (6 ml).The mixture was stirred for 3 hrs. The reaction mixture was diluted withether. A saturated aq. solution of sodium bicarbonate (30 ml) whereinsodium thiosulfate (2.26 g) was dissolved was added to the dilutedsolution. The mixture was stirred for 10 mins, and extracted with EtOAc.The extract was washed, dried and evaporated. The residue was purifiedby column chromatography on silica gel (hexane - EtoAc) to give thetitle compound (238 mg) having the following physical data:

TLC:Rf 0.25 (EtOAc);

IR:ν 3000˜2930, 1765, 1630, 1435, 1370, 1200, 1125, 1085, 1015 cm⁻¹

EXAMPLE 14 Synthesis of3-[(2S)-1-[3-(N-benzyl-N-methylcarbamoyl)propanoyl]pyrrolidin-2-yl]-3-oxo-2,2-difluoropropionicacid monohydrate ##STR121##

By the same procedure as is described in Example 3, using3-[(2S)-1-[3-(N-benzyl-N-methylcarbamoyl)propanoyl]pyrrolidin-2-yl]-3-oxo-2,2-difluoropropionicacid ethyl ester, the title compound having the following physical datawas given:

TLC:Rf 0.4. EtOAc:AcOH:H₂ O=3:1:1);

IR (CHCl₃ Solution):

ν2990, 2920, 1755, 1625, 1440, 1120 cm⁻¹

EXAMPLE 15 Synthesis of(1RS)-1-[(2S)-1-[3-(N-benzyl-N-methylcarbamoyl)propanoyl]pyrrolidin-2-yl)-propan-1-ol ##STR122##

A solution of(2S)-1-[3-(N-benzyl-N-methylcarbamoyl)propanoyl]pyrrolidin-2-al (700 mg)in THF (5 ml) was cooled to -25° C. A solution of ethyl magnesiumchloride in THF (2M, 1.5 ml) was added dropwise to the solution. Themixture was stirred for 30 mins at the same temperature, and for 30 minsat 0° C. and further 1 hr. at room temperature. After reaction, asaturated aq. solution of ammonium chloride was added to the mixture.The oily layer separated was washed, dried and evaporated. The residuewas purified by column chromatography on silica gel (EtOAc - CH₃ OH) togive the title compound (270 mg) having the following physical data:

TLC:Rf 0.47 (EtOAc:CH₃ OH=9:1));

IR:ν3350, 1600, 1400, 1220, 1090, 720, 680 cm⁻¹

EXAMPLE 15(a)

By the same procedure as is described in example 15, the title compoundhaving the physical data shown in table VII was obtained.

                                      TABLE VII                                   __________________________________________________________________________     ##STR123##                                                                   Example                                                                       No.  Fromula      Name            TLC       IR (νcm.sup.-1)                __________________________________________________________________________    15 (a)                                                                              ##STR124##  (1RS)-1-[(4R)-3-[1-(3- phenylpropanoyl)pieridin-2-yl                          carbonyl]thiazolidin-4-yl]propan- 1-ol                                                        Rf 0.30 (EtOAc:hexane                                                                   3400, 1610, 1400, 1240, 1150,                                                 1000, 740, 670                    __________________________________________________________________________

EXAMPLE 16 Synthesis of 1-1(2S)-1-[3-(N-benzyl-N-methylcarbamoyl)propanoyl) pyrrolidin-2-yl)propan-1-one ##STR125##

By the same procedure as is described in example 2, using(1RS)-1-[(2S)-1-[3-(N-benzyl-N-methylcarbamoyl)propanoyl]pyrrolidin-2-yl]propan-1-ol,the title compound having the following physical data was given:

TLC:Rf 0.49 (CH₂ Cl₂ :CH₃ OH=19:1);

IR:ν 1700, 1620, 1400, 1100, 720, 670 cm⁻¹

EXAMPLE 17 Synthesis of(1RS)-1-phenyl-1-[(2S)-1-[3-(N-benzyl-N-methylcarbamoyl)propanoyl)pyrrolidin-2-yl]methanol ##STR126##

A solution of(2S)-1-[3-(N-benzyl-N-methylcarbamoyl)propanoyl]pyrrolidin-2-al (200 mg)in THF (5 ml) was cooled to -25° C. A solution of phenyl magnesiumbromide in THF (2M, 0.49 ml) was added dropwise to the solution. Thereaction solution was stirred for 30 mins, at the same temperature, andfor 30 mins at 0° C. A saturated aq. solution of ammonium chloride wasadded to the reaction solution. The mixture was extracted with EtOAc.The extract was washed, dried, and evaporated. The residue was purifiedby column chromatography on silica gel (EtOAc-CH₃ OH) to give the titlecompound (45 mg) having the following physical data:

TLC:Rf 0.47 (EtOAc:CH₃ OH:19:1);

IR:ν3350, 1610, 1420, 1180, 1040, 670 cm⁻¹

EXAMPLE 17(a)-17(c)

By the same procedure as is described in example 17, title compoundshaving the physical data shown in table VIII were obtained.

                                      TABLE VII                                   __________________________________________________________________________     ##STR127##                                                                   Example                                                                       No.  Formula         Name              Formula   IR (νcm.sup.-1)           __________________________________________________________________________    17 (a)                                                                              ##STR128##     (1RS)-1-phenyl-1-[(4R)-3-[(4R)-3- (4-phenylbutanoyl)t                         hiazolidin-4- ylcarbonyl]thiazolidin-4- yl]methanol                                             Rf 0.31 (EtOAc:hexane                                                                   (KBr tablet) 3400, 1620,                                                      1400, 730, 690               17 (b)                                                                              ##STR129##     (1RS)-1-phenol-1-[(4R)-3-[3-(N- benzyl-N-methylcarbam                         oyl) propanoyl]thiazolidin-4- yl]methanol                                                       Rf 0.25 (EtOAc:hexane                                                                   (KBr tablet) 3350, 1610,                                                      1390, 720, 690               17 (c)                                                                              ##STR130##     (1RS)-1-phenyl-1-[(4R)-3-[(2RS)-2- (4-phenylbutanoyla                         mino)-3- methylbutanoyl]thiazolidin-4- yl]methanol                                              Rf 0.59 (EtOAc:hexane                                                                   (KBr tablet) 3400, 3270,                                                      1610, 1410, 730,             __________________________________________________________________________                                                     690                      

EXAMPLE 8 Synthesis of [(2S)-1-[3-(N-benzyl-N-methylcarbamoyl)propanoyl)pyrrolidin-2-yl)dimethoxymethane ##STR131##

α-Camphorsulphonic acid (11.6 mg) was added to a solution of(2S)-1-[3-(N-benzyl-N-methylcarbamoyl)propanoyl]pyrrolidin-2-al (160 mg)in methanol (2 ml). The mixture was stirred for 3 hrs. at roomtemperature. After reaction, the mixture was extracted with EtOAc. Theextract was washed, dried, and evaporated. The residue was purified bycolumn chromatography on silica gel (EtOAc--CH₂ Cl₂ --CH₃ OH) to givethe title compound (156 mg) having the following physical data:

TLC:Rf 0.42 (EtOAc:CH₂ Cl₂ :CH₃ OH=9:5:1);

IR:ν 2900, 1620, 1400, 1180, 1110, 1050, 960, 730, 690 cm⁻¹

EXAMPLE 18(a)-18(b)

By the same procedure as is described in example 18, title compoundshaving the physical data shown in table IX were obtained.

                                      TABLE IX                                    __________________________________________________________________________     ##STR132##                                                                   Example                                                                       No.  R-           Name             TLC       IR (νcm.sup.-1)               __________________________________________________________________________    18 (a)                                                                              ##STR133## [(4R)-3-[3-(N-benzyl-N- methylcarbamoyl)propanoly]                            thiazolidin-4-yl]dimethoxymethane                                                              Rf 0.38 (EtOAc: CH.sub.2 Cl.sub.2 :                                           CH.sub.3 OH) = 9:5:1)                                                                   2910, 2820,                                                                   1730, 1650˜1620, 1400,                                                  1105, 1060, 970, 730, 690         18 (b)                                                                             φ-(CH.sub.2).sub.9                                                                    [(4R)-3-(10-phenyldecanoyl)                                                                    Rf 0.58   2900, 2830, 1640,                                  thiazolidin-4-yl]dimethoxymethane                                                              (EtOAc:hexane) =                                                                        1420, 1390, 1100,                                                   1:1)      1060, 740, 680                    __________________________________________________________________________

EXAMPLE 19 Synthesis of2-[(2S)-1-[3-(N-benzyl-N-methylcarbamoyl)propanoyl]pyrrolidin-2-yl]-1,3-dioxolane##STR134##

Ethylene glycol (0.3 ml), p-toluenesulphonic acid (1 mg) were added to asolution of (2S)-1-[3-(N-benzyl-N-methylcarbamoyl)propanoyl]pyrrolidin-2-al (164 mg) in benzene (3 ml). The mixture wasrefluxed for 1 hr. The reaction solution was poured into a saturated aq.solution of sodium bicarbonate. The mixture was extracted with benzene.The extract was washed, dried, and evaporated. The residue was purifiedby column chromatography on silica gel (CH₃ OH-EtOAc-CH₂ Cl₂) to givethe title compound (79 mg) having the following physical data:

TLC:Rf 0.35 (CH₃ OH:EtOAc:CH₂ Cl₂ =1:9:5));

IR:ν2900, 2850, 1720, 1620, 1400, 1110, 1050, 720, 680 cm⁻¹

EXAMPLE 20 Synthesis of 3-[(2S)-1-[3-(N-benzyl-N-methylcarbamoyl)propanoyl]pyrrolidin-2-yl]-3-oxopropionic acid monohydrate ##STR135##

By the same procedure as is described in example 3, using the compoundprepared in example 11, the title compound having the following physicaldata was obtained:

TLC:Rf 0.62 (EtOAc:AcOH:H₂ O=3:1:1);

IR (CHCl₃ Solution):

ν3000, 1725, 1630, 1440, 1410, 1250˜1210 cm⁻¹

FORMULATION EXAMPLE

The following components were admixed by a conventional method andpunched out to obtain 100 tablets each containing 50 mg of activeingredient.

    ______________________________________                                        (2RS)-2-[(2S)-N-[3-(N-benzyl-N-methylcarbamoyl)                                                          5      g                                           propanoyl]pyrrolidin-2-yl]-2-hydroxyacetic acid                               ethyl ester                                                                   Cellulose calcium glycolate                                                                              0.2    g                                           (disintegrating agent)                                                        Magnesium stearate         0.1    g                                           (lubricating agent)                                                           Microcrystaline cellulose  4.7    g                                           ______________________________________                                    

What is claimed is:
 1. A pyrrolidine derivative of the formula:##STR136## wherein Z represents a methylene group, R represents thegeneral formula:

    G--E--D--B--A--

wherein A represents a linkage which contains no atom, an alkylene groupof from 1 to 6 carbon atoms(s), an alkenylene group of from 2 to 6carbon atoms, a group of the formula: ##STR137## wherein Y represents analkylene group of from 1 to 4 carbon atom(s) or an alkenylene group offrom 2 to 4 carbon atoms, a saturated hydrocarbon ring of from 4 to 7carbon atoms or a heterocyclic mono ring containing 3 to 7 ring membersincluding 1 or 2 hetero atom(s) selected from N, O and S atoms which maybe partially or fully saturated or aromatic, B represents a linkagewhich contains no atom or an alkylene group of from 1 to 6 carbonatom(s), D represents a group of the formula:

    --NR.sup.1 --CO--

wherein R¹ represents a hydrogen atom, an alkyl group of from 1 to 6carbon atom(s), a phenyl group or a benzyl group, E represents a linkagewhich contains no atom, an alkylene group of from 1 to 8 carbon atom(s)or an alkylene group of from 1 to 8 carbon atom(s) substituted or by aphenyl or benzyl group, G represents a mono-, bi- or tri-carbocyclicring(s) containing not more than 15 carbon atoms which may be partiallyor fully saturated or aromatic, or mono-, bi- or tri-heterocyclicring(s) containing not more than 15 ring members including carbon and 1or 2 hetero atoms selected from N, O and S atoms which may be partiallyor fully saturated or aromatic wherein said carbocyclic or heterocyclicring(s) represented by G is unsubstituted or substituted by 1-3 of analkyl group of from 1 to 6 carbon atoms(s), an alkoxy group of from 1 to6 carbon atom(s), a halogen atom, a trifluoromethyl group or a nitrogroup, and L represents a group of the formula:

    --CO--COR.sup.2

    --CO--CH.sub.2 --COR.sup.2

    --CO--CF.sub.2 --COR.sup.2

    --CO--CO--NR.sup.5 R.sup.6

or

    --CO--CH.sub.2 --CO--NR.sup.5 R.sup.6

wherein, R² represents a hydrogen atom, a hydroxy group, an alkyl groupof from 1 to 6 carbon atom(s), an alkoxy group of from 1 to carbonatom(s), a phenyl group, an alkyl group of from 1 to 6 carbon atom(s)substituted by a phenyl group, or an alkoxy group of from 1 to 6 carbonatom(s) substituted by a phenyl group, R⁵ and R⁶ independently representa hydrogen atom, an alkyl group of from 1 to 6 carbon atom(s), a phenylgroup, or an alkyl group of from 1 to 6 carbon atom(s) substituted by aphenyl group, with the proviso that the following compounds areexcluded:(i) compounds wherein both of A and B are a linkage whichcontains no atom or a non-toxic salt or hydrate thereof.
 2. A compoundaccording to claim 1, wherein G is phenyl, naphthyl or fluorenyl groupwhich is unsubstituted or substituted.
 3. A compound according to claim1, of general formula: ##STR138## wherein L¹ represents a group ofgeneral formula:

    --CO--CH.sub.2 --COR.sup.2

    --CO--CF.sub.2 --COR.sup.2

    --CO--CO--NR.sup.5 R.sup.6

or wherein all of the symbols are the same meaning as defined inclaim
 1. 4. A compound according to claim 1 or 3, whichis:3-((2S)-1-{3-(N-benzyl-N-methylcarbamoyl)propanoyl)pyrrolidin-2-yl)-3-oxopropionicacid or ethyl ester thereof,3-((2S)-1-{3-(N-benzyl-N-methylcarbamoyl)propanoyl)pyrrolidin-2-yl}-3-oxo-2,2-difluoropropionic acid or ethyl ester thereof,2-{(2S)-1-{3-(N-benzyl-N-methylcarbamoyl)propanoyl)pyrrolidin-2yl}-2-oxo-N-ethylacetamide,2-{(2S-1-{3-(N-benzyl-N-methylcarbamoyl)propanoyl}pyrrolidin-2-yl}-2-oxoacetamideor2-{(2S)-1-{3-(N-benzyl-N-methylcarbamoyl)propanoyl)pyrrolidin-2-yl}-2-oxo-N-methyl-N-benzylacetamide.5. A compound according to claim 1 of general formula: ##STR139##

    --CO--COR.sup.2

wherein all of the symbols are the same meaning as defined in claim 1.6. A compound according to claim 1 or 5, whichis:2-{(2S)-1-{3-(N-benzyl-N-methylcarbamoyl)propanoyl}pyrrolidin-2-yl)-2-oxoaceticacid, 2-{(2S)-1-{3-{N-(4-chlorophenylmethyl)carbamoyl}propanoyl}pyrrolidin-2-yl}-2-oxoacetic acid,2-{(2S)-1-{3-{N-(9-fluorenyl)carbamoyl}propanoyl}pyrrolidin-2-yl}-2-oxoacetic acid,2-{(2S)-1-{3-{N-(4-trifluoromethylphenylmethyl)-N-phenylcarbamoylpropanoyl}pyrrolidin-2-yl}-2-oxoacetic acid,2-{(2S)-1-(3-(N-benzyl-N-t-butylcarbamoyl)propanoyl}pyrrolidin-2-yl}-2-oxoacetic acid,2-{(2S)-1-{3-(N-benzyl-N-phenylcarbamoyl}propanoyl}pyrrolidin-2-yl}-2-oxoaceticacid, 2-{(2S)-1-{3-{N-(1-naphthy)methyl-N-methylcarbamoyl)propanoyl)pyrrolidin-2-yl)-2-oxocetic acid,2-{(2S)-1-{3-{N-(2,4-dichlorophenylmethyl)carbamoyl}propanoyl}pyrrolidin-2-yl)-2-oxoacetic acid,2-{(2S-1-{3-(N-(2-naphthyl)methyl-N-methylcarbamoyl}propanyl}pyrrolidin-2-yl}-2-oxoaceticacid, 2-{(2S)-1-{(1RS,2R)-2-(N-benzylcarbamoyl)cyclopentanecarbonyl}pyrrolidin-2-yl}-2-oxoaceticacid,2-{(2S)-1-{3-{N-(4-methylphenylmethyl)carbamoyl}propanoyl}pyrrolidin-2-yl)-2-oxoaceticacid,2-{(2S)-1-{3-{N-(4-chlorophenylmethyl)-N-phenylcarbamoyl}propanoyl}pyrrolidin-2-yl)-2-oxoaceticacidor2-{(2S)-1-{3-{N-(4-chlorophenylmethyl)-N-methylcarbamoyl}propanoyl}pyrrolidin-2-yl}-2-oxoaceticacid2-{(2S)-1-(3-(N-benzyl-N-methylcarbamoyl)propanoyl}pyrrolidin-2-yl}-2-hydroxyaceticacid, 2-{(2S)-1-{3-(N-(4-chlorophenylmethyl)carbamoyl}propanoyl}pyrrolidin-2-yl)-2-hydroxyacetic acid,2-{(2S)-1-{3-{N-(9-fluorenyl)carbamoyl}propanoyl}pyrrolidin-2-yl}-2-hydroxyaceticacid,{(2S)-1-{3-(N-benzyl-N-methylcarbamoyl)propanoyl}pyrrolidin-2-yl}dimethoxymethane,2-{(2S)-1-{3-(N-benzyl-N-methylcarbamoyl)propanoyl}pyrrolidin-2-yl}-2-1,3-dioxolan,(1RS)-1-{(2S)-1-(3-(N-benzyl-N-methylcarbamoyl)propanoyl}pyrrolidin-2-yl}propan-1-ol or(1RS)-1-phenyl-1-{(2S)-1-{3-(N-benzyl-N-methylcarbamoyl)propanoyl}pyrrolidin-2-yl)methanol].
 7. A compound whichis:2-{(2S)-1-{(1RS, 2R)-2-(3-phenylpropanoyl)cyclopentanecarbonyl}pyrrolidin-2-yl}-2-oxoacetic acid or ethyl esterthereof.
 8. A compound whichis:2-{(2S)-1-{3-(4-(4-phenylbutoxy)phenyl}propenoyl}pyrrolidin-2-yl}-2-oxoaceticacid or ethyl ester thereof.
 9. A pharmaceutical composition fortreating amnesia which comprises, as active ingredient, a therpeuticallyeffective amount of pyrrolidine derivative of the following generalformula (I) and pharmaceutically acceptable carrier and/or coating:##STR140## wherein Z represents a methylene group, R represents thegeneral formula:

    G--E--D--B--A--

wherein A represents a linkage which contains no atom, an alkylene groupof from 1 to 6 carbon atoms(s), an alkenylene group of from 2 to 6carbon atoms, a group of the formula: ##STR141## wherein Y represents analkylene group of from 1 to 4 carbon atom(s) or an alkenylene group offrom 2 to 4 carbon atoms, a saturated hydrocarbon ring of from 4 to 7carbon atoms or a heterocyclic mono ring containing 3 to 7 ring membersincluding 1 or 2 hetero atom(S) selected from N, O and S atoms which maybe partially or fully saturated or aromatic, B represents a linkagewhich contains no atom or an alkylene group of from 1 to 6 carbonatom(s), D represents a group of the formula:

    --NR.sup.1 --CO--

wherein R¹ represents a hydrogen atom, an alkyl group of from 1 to 6carbon atom(s), a phenyl group or a benzyl group, E represents a linkagewhich contains no atom, an alkylene group of from 1 to 8 carbon atom(s)or an alkylene group of from 1 to 8 carbon atom(s) substituted or by aphenyl or benzyl group, G represents a mono-, bi- or tri-carbocyclicring(s) containing not more than 15 carbon atoms which may be partiallyor fully saturated or aromatic, or mono-, bi- or tri-heterocyclicring(s) containing not more than 15 ring members including carbon and 1or 2 hetero atoms selected from N, O and S atoms which may be partiallyor fully saturated or aromatic wherein said carbocyclic or heterocyclicring(s) represented by G is unsubstituted or substituted by 1-3 of analkyl group of from 1 to 6 carbon atoms(s), an alkoxy group of from 1 to6 carbon atom(s), a halogen atom, a trifluoromethyl group or a nitrogroup, and L represents a group of the formula:

    --CO--COR.sup.2

    --CO--CH.sub.2 --COR.sup.2

    --CO--CF.sub.2 --COR.sup.2

    --CO--CO--NR.sup.5 R.sup.6

or

    --CO--CH.sub.2 --CO--NR.sup.5 R.sup.6

wherein, R² represents a hydrogen atom, a hydroxy group, an alkyl groupof from 1 to 6 carbon atom(s), an alkoxy group of from 1 to 6 carbonatom(s), a phenyl group, an alkyl group of from 1 to 6 carbon atom(s)substituted by a phenyl group, or an alkoxy group of from 1 to 6 carbonatom(s) substituted by a phenyl group, R⁵ and R⁶ independently representa hydrogen atom, an alkyl group of from 1 to 6 carbon atom(s), a phenylgroup, or an alkyl group of from 1 to 6 carbon atom(s) substituted by aphenyl group, with the proviso that compounds wherein both of A and Bare a linkage which contains no atom are excluded; or a non-toxic saltor hydrate thereof.
 10. A method for prevention and treatment of amnesiawhich comprises administration of a therapeutically effective amount ofpyrrolidine derivative of the general formula (I): ##STR142## wherein Zrepresents a methylene group, R represents the general formula:

    G--E--D--B--A--

wherein A represents a linkage which contains no atom, an alkylene groupof from 1 to 6 carbon atoms(s), an alkenylene group of from 2 to 6carbon atoms, a group of the formula: ##STR143## wherein Y represents analkylene group of from 1 to 4 carbon atom(s) or an alkenylene group offrom 2 to 4 carbon atoms, a saturated hydrocarbon ring of from 4 to 7carbon atoms or a heterocyclic mono ring containing 3 to 7 ring membersincluding 1 or 2 hetero atom(s) selected from N, O and S atoms which maybe partially or fully saturated or aromatic, B represents a linkagewhich contains no atom or an alkylene group of from 1 to 6 carbonatom(s), D represents a group of the formula:

    --NR.sup.1 --CO--

wherein R¹ represents a hydrogen atom, an alkyl group of from 1 to 6carbon atom(s), a phenyl group or a benzyl group, E represents a linkagewhich contains no atom, an alkylene group of from 1 to 8 carbon atom(s)or an alkylene group of from 1 to 8 carbon atom(s) substituted or by aphenyl or benzyl group, G represents a mono-, bi- or tri-carbocyclicring(s) containing not more than 15 carbon atoms which may be partiallyor fully saturated or aromatic, or mono-, bi- or tri-heterocyclicring(s) containing not more than 15 ring members including carbon and 1or 2 hetero atoms selected from N, O and S atoms which may be partiallyor fully saturated or aromatic wherein said carbocyclic or heterocyclicring(s) represented by G is unsubstituted or substituted by 1-3 of analkyl group of from 1 to 6 carbon atoms(s), an alkoxy group of from 1 to6 carbon atom(s), a halogen atom a trifluoromethyl group or a nitrogroup, and L represents a group of the formula:

    --CO--COR.sup.2

    --CO--CH.sub.2 --COR.sup.2

    --CO--CF.sub.2 --COR.sup.2

    --CO--CO--NR.sup.5 R.sup.6

or

    --CO--CH.sub.2 --CO--NR.sup.5 R.sup.6

wherein, R² represents a hydrogen atom, a hydroxy group, an alkyl groupof from 1 to 6 carbon atom(s), an alkoxy group of from 1 to 6 carbonatom(s), a phenyl group, an alkyl group of from 1 to 6 carbon atom(s)substituted by a phenyl group, or an alkoxy group of from 1 to 6 carbonatom(s) substituted by a phenyl group,, R⁵ and R⁶ independentlyrepresent a hydrogen atom, an alkyl group of from 1 to 6 carbon atom(s),a phenyl group, or an alkyl group of from 1 to 6 carbon atom(s)substituted by a phenyl group, with the proviso that compounds whereinboth of A and B are a linkage which contains no atom are excluded; or anon-toxic salt or hydrate thereof.